Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort

Abstract

SummaryBackgroundCo-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults.MethodsParticipants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per μL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779.Findings3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0·65, 95% CI 0·50–0·85; p=0·001). Mortality risk reduction on ART was substantial to 12 weeks (0·41, 0·27–0·65), sustained from 12–72 weeks (0·56, 0·37–0·86), but not evident subsequently (0·96, 0·63–1·45; heterogeneity p=0·02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0·74, 0·63–0·88; p=0·0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0·86, 0·69–1·07; p=0·17), CD4 cell count (difference vs non-users, −3 cells per μL [−12 to 6]; p=0·50), or BMI (difference vs non-users, −0·04 kg/m2 [−0·20 to 0·13); p=0·68].InterpretationOur results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa.FundingUK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis

“…28 This effect was maintained throughout a follow-up period of 5 years. In addition, Walker et al also reported that cotrimoxazole reduced the odds of new or recurrent WHO clinical stage 3 or 4 disease events (OR: 0.85; 95% CI: 0.74-0.98), 28 whereas Miiro et al reported a trend towards lower all-cause morbidity (relative risk, RR: 0.66; 95% CI: 0.41-1.06), although all-cause morbidity was undefined.…”

“…28 This effect was maintained throughout a follow-up period of 5 years. In addition, Walker et al also reported that cotrimoxazole reduced the odds of new or recurrent WHO clinical stage 3 or 4 disease events (OR: 0.85; 95% CI: 0.74-0.98), 28 whereas Miiro et al reported a trend towards lower all-cause morbidity (relative risk, RR: 0.66; 95% CI: 0.41-1.06), although all-cause morbidity was undefined. 35 A trial identified during the review of references of studies that met the inclusion criteria found that the risk of both malaria (RR: 0.04; 95% CI: 0.01-0.17) and diarrhoea (RR: 0.56; 95% CI: 0.43-0.77) was lower among Ugandans on ART who were randomized to cotrimoxazole than among those who were not.…”

“…Of the nine, seven reported an estimate for the effect of cotrimoxazole on mortality, [28][29][30][31][32][33][34] whereas three reported an estimate for the effect on morbidity. 28,35,36 Two studies also reported the preventive effect on malaria.…”

“…Of the nine, seven reported an estimate for the effect of cotrimoxazole on mortality, [28][29][30][31][32][33][34] whereas three reported an estimate for the effect on morbidity. 28,35,36 Two studies also reported the preventive effect on malaria. 28,36 Assessment of publication bias indicated that three studies [28][29][30] were of high methodological quality, while the other six [31][32][33][34][35][36] were of moderate methodological quality (Table 4, available at: http://www.who.…”

“…28,35,36 Two studies also reported the preventive effect on malaria. 28,36 Assessment of publication bias indicated that three studies [28][29][30] were of high methodological quality, while the other six [31][32][33][34][35][36] were of moderate methodological quality (Table 4, available at: http://www.who. int/bulletin/volumes/90/2/11-093260).…”